Harmony of triple forces: Ionic bonding, hydrogen bonding, and halogen bonding
An innovative technique to make iodine more functional and use it as a catalyst: Researchers have developed a new method to synthesize optically active lactone useful for drug development.



In their joint research, Professor Masayoshi Yamanaka of Rikkyo University’s Department of Chemistry and Professor Takayoshi Arai of Chiba University’s Department of Chemistry succeeded in developing a catalyst that facilitates steric selectivity reactions in a single metal complex by combining the processes of ionic bonding, hydrogen bonding, and halogen bonding (See Figure 1) (Arai also heads Soft Molecular Activation Research Center and Chiba Iodine Research Innovation Center).

<Outlines of the Research>

Figure 1 Cooperative activation using ionic bonding, hydrogen bonding, and halogen bonding in metal-catalyzed asymmetric halolactonization.

<Background and purposes>

Figure 2 Three bonding powers fused in this study

The purpose of catalysts is essentially to obtain the required compounds by recognizing and activating reactive substrates or reagents. Particularly, chemistry dealing with asymmetric catalysts which synthesize, with steric selectivity, complexly functionalized compounds such as medicine requires a high level of molecular recognition.

For instance, metal catalysts are very attractive because they exhibit peculiar characteristics which are not seen in organic compounds alone (See Figure 2a). Furthermore, using complex catalysts with ligands that allow molecular recognition has made it possible to build complicated molecular frameworks. However, as this process uses environmentally harmful metal salts, it has become a major challenge to attain high levels of activation even by reducing the amount of catalysts as much as possible.

On the other hand, enzymes which play the roles of catalysts in our body perform efficient molecular recognition and activation using hydrogen bonding (See Figure 2b). This type of bonding is widely used in laboratory flask experiments to activate reaction substrates – particularly in the organic catalyst fields which do not use metals – as the most fundamental and effective catalyst mechanism.

To ensure state-of-the-art catalytic chemistry, incorporating the exceptional physiological function of the human body is essential. Fusing metal complex catalysis and organic catalysis is a subject that is actively being explored in research currently.

Figure 3: Halogen bonding

However, is a mere fusion of two subcategories of chemistry (for instance, metal complex catalysis and organic catalysis) enough to advance catalytic chemistry? It is necessary to actively introduce innovative ideas in the field of catalytic chemistry to synthesize the desired structures of organic molecules with limitless potentials.

Accordingly, we consider halogen bonding – a new, third area of high potentiality. (See Figure 2c) Halogen bonding has attracted much attention as a new interaction with a clear direction which can have applications in catalytic chemistry and functional molecule creations. It was, however, difficult to achieve productive levels of chemical structural recognition, such as steric selectiveness, as halogen bonding is formed by a positive charge that exists behind an R-X bond in a molecular framework. (See Figure 3)

<Research results>

Figure 4: The zinc trinuclear complex catalyst (tri-Zn)

Halolactonization, having unsaturated carboxylic acid as the substrate, is significant in that it can promptly lead to halogen-carbon bonding, which is capable of realizing lactone frameworks seen in chemical compounds such as drugs and natural substances and converting various chemical structures. In 2014, we succeeded in developing an optically active zinc trinuclear complex catalyst which helps obtain the desired iodolactonization with world-record, impeccable steric selectivity. The research result is published in Chem. Comm., a chemistry journal. (1,2)

The zinc trinuclear complex catalyst (tri-Zn), which can easily be made from optically active Bis(aminoimino)biphenol ligands and zinc acetate, has three zinc atoms. (See Figure 4)

Figure 5: Tri-Zn-catalyzed asymmetric iodolactonization

The tri-Zn complex exhibits extremely high catalytic characteristics to attain iodolactonization: only 1 mol% of it helps attain optically active iodolactonization (See Figure 5).

Figure 6: Reaction transition state in which ionic bonding, hydrogen bonding, and halogen bonding work in tandem.

The researchers identified the structure of the tri-Zn complex by X-ray crystallography. Their nuclear magnetic resonance (NMR) experiments and electrospray ionization-mass spectrometry (ESI-MS) analyses demonstrated that the acetate ion positioned outside the tri-Zn complex serves as a base and that carboxylic acid, the substrate, becomes zinc carboxylate, facilitating reactions in the tri-Zn-complex-catalyzed asymmetric iodolactonization. It is known that iodolactonization using N-Iodosuccinimide (NIS) can be accelerated by adding Iodine (I2). For instance, through iodolactonization, as shown in Figure 5, the desired substance can be obtained at 7% in chemical yields (97%ee) without the use of I2. Furthermore, the ultraviolet visible absorption spectroscopy (UV-VIS) analyses suggested a 1:1 interaction of the tri-Zn complex with NIS-I2.

DFT calculations were performed based on these findings to determine the transition state (See Figure 6). In the transition state, it was indicated that the substrate, zinc carboxylate, is activated by NIS-I2 reagent and that NIS is hydrogen-bounded with a ligand.

The catalyst is the world’s first catalyst to facilitate steric selective reactions by combining three types of bonding – ionic bonding, hydrogen bonding, and halogen bonding in a single metal complex (See Figure 6).

Figure 7: Catalytic cycle of asymmetric iodolactonization reactions with the use of tri-Zn complex

Close examinations of the transition state in Figure 6, however, indicate that I2 is what iodizes olefin and not the iodine contained in NIS. In actual reactions, as shown in Figure 5, they used 1.1 equivalent of NIS and only 0.2 equivalent of I2. Why was 0.2 equivalent of I2 sufficient for causing the transition?

Figure 7 shows the researchers’ hypothesis on the catalytic cycle of asymmetric halolactonization reactions with the use of the tri-Zn complex. First, an acetate anion of the zinc trinuclear complex (A) exchanges with a substrate to generate zinc carboxylate (B). The olefin section of zinc carboxylate (B) is activated by the complex of NIS and iodine, reaching the aforementioned transition state (C) to help attain the desired iodolactonization. During the process, the olefin section is directly activated by I2 and not NIS. Therefore, if the reactions proceed as indicated in the curly arrows, I2 is regenerated. Therefore, 0.2 equivalent of I2 is sufficient to facilitate the reactions.

Figure 8: Asymmetric, 5-membered ring iodolactones by catalyst via antisymmetrization

Furthermore, the structure of the transition state indicates that the tri-Zn complex sterically controls nucleophilic carboxylic acid and electrophilic iodonium ion. Thus, the researchers decided to use this catalyst to have more complicated asymmetry iodolactonization.

Iodolectonization using a tri-Zn complex as catalyst on asymmetry substrate 1 will trigger reactions which progress with high diastereoselectivity, successfully resulting in the generation of 5-membered ring lactone 2 with a high asymmetric yield (See Figure 8).

The optically active 5-membered ring lactone 2 is highly usable for syntheses because it still contains an iodinated alkyl group and unreacted olefins in its molecules (See Figure 9).

Figure 9: Usefulness of optical active 5-membered ring iodolactones via antisymmetrization

<Creativity and advancement>

There are only a few cases that have succeeded in attaining steric selective reactions by introducing halogen bonding to asymmetric catalysts. This research group is a pioneer in the research field. It is the world’s first catalyst that facilitates steric selective reactions by ionic bonding, hydrogen bonding, and halogen bonding working in tandem on a single metal complex. The study also elucidated that the actual iodizing agent for iodolactonization is not NIS but pure iodine.

<Social contribution and ripple effects>

If catalysts with halogen bonding, working in tandem with other types of bonding, and asymmetric reactions using such catalysts are developed, it will consequently be possible to obtain asymmetric synthesis of molecules containing diverse functional groups suitable for soft chemistry – this will represent a major academic feat. If halogen bonding in a solution can be manipulated as desired, it is expected to lead to the creation of new functional molecules such as medicines and sensors based on halogen bonding and other types of bonding. The present study is part of the endeavors by Chiba Iodine Resource Innovation Center to make iodine more functional.

The results of this study are published in iScience, an open access journal published by Cell-Press.


1) Arai, T.; Sugiyama, N.; Masu, H.; Kado, S.; Yabe, S.; Yamanaka, M. Chem. Comm. 2014, 42, 8287.
2) Arai, T.; Kojima, T.; Watanabe, O.; Itoh, T.; Kanoh, H. ChemCatChem. 2015, 7, 3234.


This study was funded by the Ministry of Education, Culture, Sports, Science and Technology’s grant-in-aid for scientific research on innovative area (FY2015–2019), “Precise formation of a catalyst having a specified field for use in extremely difficult substrate conversion reactions.”

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